Submissions for variant NM_001127222.2(CACNA1A):c.4897G>A (p.Asp1633Asn)

dbSNP: rs1555740805

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000518921	SCV000618426	pathogenic	not provided	2023-02-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31785789, 29165669, 19344873, 33798445, 34445196)
Ambry Genetics	RCV000624265	SCV000742698	pathogenic	Inborn genetic diseases	2024-06-10	criteria provided, single submitter	clinical testing	The c.4900G>A (p.D1634N) alteration is located in coding exon 31 of the CACNA1A gene. This alteration results from a G to A substitution at nucleotide position 4900, causing the aspartic acid (D) at amino acid position 1634 to be replaced by an asparagine (N). ; however, it is unlikely to be causative of CACN1A-related spinocerebellar ataxia. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation or reported as heterozygous in multiple individuals with features consistent with episodic ataxia, type 2 and CACNA1A-related neurologic disorders (Galatolo, 2021; Courage, 2021; Lipman, 2022; DECIPHER). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV003985374	SCV001251609	likely pathogenic	CACNA1A-related disorder	2020-01-24	criteria provided, single submitter	clinical testing	The CACNA1A c.4900G>A (p.Asp1634Asn) variant is a missense variant. It is reported as a de novo variant, though without confirmed parentage, in one individual in the DECIPHER database (Firth et al. 2009, patient 259278). The reported phenotype of this individual is consistent with CACNA1A-related disorders and includes global developmental delay, intellectual disability, sleep disturbance, unsteady gait, falls, behavioral abnormalities, brachycephaly, strabismus, and bilateral single transverse palmar creases. The p.Asp1634Asn variant has also been identified by clinical laboratories in individuals with neurodevelopmental phenotypes consistent with CACNA1A-related disorders and submitted to the ClinVar database (Landrum et al. 2018); however these cases are not reported in the published literature and clinical details are limited. This variant is not found in the Genome Aggregation Database in a region of good sequencing coverage, so the variant is presumed to be rare. The p.Asp1634Asn variant occurs at a conserved residue in the S3 transmembrane segment of domain IV of the voltage-dependent P/Q-type calcium channel subunit alpha-1A protein, though the function of this region is unknown. In silico predictions suggest a damaging consequence, however this has not been evaluated experimentally. Based on the collective evidence and the application of ACMG criteria, the p.Asp1634Asn variant is classified as likely pathogenic for CACNA1A-related disorders.
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001644622	SCV001519108	pathogenic	Episodic ataxia type 2	2021-01-04	criteria provided, single submitter	research
Wendy Chung Laboratory, Columbia University Medical Center	RCV002227176	SCV002506524	likely pathogenic	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 52	2022-03-20	criteria provided, single submitter	clinical testing